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Methodological considerations for observational studies of treatment effectiveness in neurology: a clinician’s guide
  1. Tomas Kalincik1,2,
  2. Izanne Roos1,2,
  3. Sifat Sharmin1,2,
  4. Charles B Malpas1,2
  1. 1CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
  2. 2Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  1. Correspondence to Professor Tomas Kalincik, Neuroimmuinology Centre, 635 Elizabeth St, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC 3000, Australia; tomas.kalincik{at}


Data from cohorts, registries, randomised trials, electronic medical records and administrative claims databases have increasingly been used to inform the use of therapies for neurological diseases. While novel sophisticated methods are enabling us to use existing data to guide treatment decisions, the complexity of statistical methodology is making appraisal of clinical evidence increasingly demanding. In this narrative review, we provide a brief overview of the most commonly used methods for evaluation of treatment effectiveness in neurology. This primer discusses complementarity of randomised and non-randomised study designs, sources of observational data, different forms of bias and the appropriate mitigation strategies, statistical significance, Bayesian approaches and provides an overview of multivariable regression models, propensity score-based models, causal inference, mediation analysis and Mendelian randomisation.


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  • Contributors TK conceptualised, drafted and edited the manuscript. IR, SS and CBM drafted and edited the manuscript.

  • Funding TK received Dame Kate Campbell Professorial Fellowship from the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne, a Fellowship from the MS Australia and an NHMRC Investigator Grant (2026836). IR received postgraduate fellowship from MS Australia. SS received research fellowship from the MSBase Foundation. CBM received research fellowship from MS Australia.

  • Competing interests TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. IR served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. CBM has received conference travel support and/or speaker fees from Merck, Novartis and Biogen.

  • Provenance and peer review Commissioned; externally peer reviewed.